Process for the preparation of tolterodine

ABSTRACT

A novel process for the preparation of tolterodine, i.e. (R)—N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamine, in the racemic form, as well as intermediates useful for its preparation.

FIELD OF THE INVENTION

The present invention relates to a novel process for the preparation oftolterodine, i.e.N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamine, in theracemic form, as well as intermediates useful for its preparation.

Tolterodine, having formula (I),

is a medicament useful in the treatment of urinary incontinence,disclosed in EP 325 571.

TECHNOLOGICAL BACKGROUND

A number of processes for the preparation of tolterodine are known. Manyof them make use of starting products hardly available or the synthesisof which requires a number of steps, so that their preparation istroublesome. By way of example, U.S. Pat. No. 5,922,914 and EP 325 571employ the intermediate 4-phenyl-chroman-2-ol. There is therefore theneed for an alternative process for the preparation of racemictolterodine, which makes use of easily available or obtainable startingproducts and operative conditions well suited to the industrialproduction, thereby decreasing costs.

SUMMARY OF THE INVENTION

It has now surprisingly been found that a compound having formula (II)

wherein X is —CH₂— and R is —N (isopropyl)₂; orX is ═CO and R is —N (isopropyl)₂ or —OR₁, wherein R₁ is an aryl or astraight or branched C₁-C₆ alkyl group, optionally substituted withphenyl, which can be prepared from easily available products, can betransformed into tolterodine or intermediates useful for its preparationby reaction with an acid agent. Similarly, tolterodine or the same aboveintermediates can be obtained by reacting a compound of formula (III)

wherein Y is a group able to provide a benzylic carbocation and Z ishydrogen or Y and Z, taken together, complete a double bond; and X and Rare as defined above, with p-cresol and an acidic agent.

The novel process for the preparation of racemic tolterodine allows toavoid using hardly available starting products, reactants and reactionconditions troublesome for the industrial production. The mainadvantages of the process of the invention will be apparent from thefollowing disclosure.

DETAILED DISCLOSURE OF THE INVENTION

The object of the invention is a process for the preparation oftolterodine or a pharmaceutically acceptable salt thereof, comprising:A) reacting a compound of formula (II)

in which when X is —CH₂— then R is —N (isopropyl)₂; or when X is ═COthen R is —N (isopropyl)₂ or —OR₁, wherein R₁ is an aryl or a straightor branched C₁-C₆ alkyl group, optionally substituted with phenyl; withan acidic agent; orB) reacting a compound of formula (III)

wherein Y is a group able to provide a benzylic carbocation and Z ishydrogen or Y and Z, taken together, complete a double bond; and X and Rare as defined above, with p-cresol and an acidic agent; to obtain,respectively, when in a compound of formula (II) or (III)

a) X is —CH₂— and R is —N(isopropyl)₂, a compound of formula (I)

i.e. tolterodine free base; or when

b) X is ═CO and R is —N(isopropyl)₂, a compound of formula (IV)

which by reduction yields tolterodine free base; or when

c) X is ═CO and R is a —OR₁, group wherein R₁ is as defined above, acompound of formula (V)

which is converted to tolterodine free base; and, if desired, convertingtolterodine free base into a pharmaceutically acceptable salt thereof.

An aryl group is for example phenyl or naphthyl, preferably phenyl.

A C₁-C₆ alkyl group is preferably a C₁-C₄ alkyl group, such as methyl,ethyl, propyl, isopropyl, butyl or tert-butyl. When substituted withphenyl, this is for example benzyl or phenylethyl.

Y as a group able to provide a benzylic carbocation is for instance ahydroxy group or a reactive derivative thereof, such as a C₁-C₆ alkyl oraryl ether, a C₁-C₆ alkyl or aryl carboxylate, a C₁-C₆ alkyl or arylsulfonate, a trifluoromethansulfonate, a sulphate, a nitrate, aphosphate, a C₁-C₆ alkyl or aryl phasphonate; an halogen atom, e.gchlorine, bromine, fluorine or iodine.

A tolterodine pharmaceutically acceptable salt can be a salt with aphysiologically acceptable organic or inorganic acid, such ashydrochloric, hydrobromic, fumaric or tartaric acids.

An acidic agent is typically a Lewis acid, preferably a mineral ororganic acid or an aqueous solution thereof, such as hydrochloric,hydrobromic, phosphoric, sulfuric, polyphosphoric, trifluoroacetic,methanesulfonic, ethanesulfonic or p-toluenesulfonic acids; preferablypolyphosphoric, sulfuric, methansulfonic or p-toluenesulfonic acids; inparticular polyphosphoric acid. or approx. 60% sulfuric acid aqueoussolution.

The rearrangement of a compound of formula (II) or process variant B)above, to obtain, according to alternatives a), b) or c), tolterodinefree base, a compound of formula (IV) or of formula (V) as definedabove, respectively, can optionally be effected in the presence of asolvent. A solvent can be an organic solvent, typically, an aromatichydrocarbon such as toluene or xylene; a chlorinated solvent, such asdichloromethane, dichloroethane, tetrachloroethylene, chlorobenzene ordichlorobenzene; or a mixture of two or more, preferably two or three,of said organic solvents; or a mixture of one or two thereof with water.An excess of the acidic agent solution itself can act as solvent. Thestoichiometric ratio of a compound of formula (II) or (III) to theacidic agent approx. ranges from 0.5 to 50, preferably approx. from 1 to5. The reaction can be carried out at a temperature approx. ranging from0° C. to the reflux temperature of the reaction mixture, preferably from20° C. to 30° C.

The stoichiometric ratio between a compound of formula (III), as definedabove, and p-cresol is approximately from 1:1 to 1:2, preferably from1:1 to about 1:1.5.

The reduction of a compound of formula (IV) to obtain tolterodine freebase can be carried out according to known methods, for example with ametal hydride complex, such as LiAlH₃ as disclosed in EP 325 571.

The conversion of a compound of formula (V) to tolterodine free base canbe carried out with known methods, for example according to EP 325 571,by a process comprising:

a′) protection of the phenol group,

b′) reduction of the ester function to primary alcohol and itsconversion to a leaving group; and

c′) reaction with diisopropylamine and cleavage of the protecting group.

A leaving group can be for example chlorine, bromine, iodine,methanesulfonyl, p-toluenesulfonyl, preferably methanesulfonyl andp-toluenesulfonyl.

The process of the invention to obtain tolterodine is preferably carriedout according to variant A), alternative a) of the process describedabove, in particular in the absence of solvent, preferably by reactionwith an acid agent selected from approx. 60% sulphuric acid aqueoussolution, polyphosphoric, methansulfonic and p-toluenesulfonic acids, inparticular from about 60% sulphuric acid aqueous solution andpolyphosphoric acid.

The conversion of tolterodine free base to a pharmaceutically acceptablesalt thereof can be carried out according to known methods.

A compound of formula (II) in which X is —CH₂— and R is —N (isopropyl)₂,which can optionally be isolated, can be obtained by reacting p-tolyloxybenzyl ether, having formula (VI), with a metallating agent and an amineof formula (VII) Lg-(CH₂)₂—N(isopropyl)₂ wherein Lg is a leaving group.

The reaction can be schematized as follows:

A metallating agent is for example a compound of formula B-M, wherein Mis an alkali or alkaline-earth metal, such as sodium, lithium, potassiumor magnesium and B is a strong organic or inorganic base. Preferredexamples of bases such are butyl lithium, magnesium diisopropylamide,lithium diisopropylamide, lithium hexamethyldisilylazide, potassiumtert-butoxide, sodium or potassium hydride, more preferably butyllithium.

In an amine of formula (VII) the leaving group Lg can be, for example,chlorine, bromine, iodine, methanesulfonyl, p-toluenesulfonyl,preferably chlorine.

The reaction can be carried out in the presence of solvent, preferablyan anhydrous organic solvent, typically a hydrocarbon, such as hexane,toluene; petroleum ether; an ether, such as tetrahydrofuran, dioxane,diethyl ether, methyl-tbutyl ether; a chlorinated solvent, such asdichloromethane, dichloroethane, tetrachloroethylene, chlorobenzene ordichlorobenzene; or a mixture of two or more, preferably two or three,of said solvents. The reaction is preferably carried out in an ethersolvent, in particular tetrahydrofuran or methyl-tbutyl ether.

The stoichiometric ratio of p-tolyloxy benzyl ether of formula (VI) tometallating agent approx. may range from 0.5 to 10. preferably from 1 to1.5. The reaction can be carried out at a temperature approx. rangingfrom −80° C. to 10° C., preferably from −15° C. to 0° C.

The stoichiometric ratio of amine of formula (VII) to the saltderivative of p-tolyloxy benzyl ether of formula (VIa) may range from0.5 to 10, preferably from 1 to 1.5. The reaction can be carried out ata temperature approx. ranging from −80° C. to the reflux temperature ofthe reaction mixture, preferably from 25° C. to 50° C.

A compound of formula (II), wherein X is ═CO and R is —N(isopropyl)₂,which can optionally be isolated, can be obtained by reacting p-cresol,or a salt thereof, and a compound of formula (VIII). The reaction whichcan be schematized as follows

is preferably carried out in the presence of a basic agent, such assodium, potassium, lithium or calcium hydroxides; sodium or potassiumcarbonates; an organic tertiary amine such as triethylamine orethyldiisopropylamine or an alkali alkoxide such as sodium methoxide orsodium ethoxide. The basic agent is preferably sodium or potassiumhydroxide, or sodium ethoxide. A p-cresol salt is for instance a saltwith one of the inorganic bases or organic tertiary amines mentionedabove.

The stoichiometric ratio of compound of formula (VIII) to p-cresol or asalt thereof approx. may range from 0.5 to 10, preferably from 1 to 1.5.

The reaction between a compound of formula (VIII) and p-cresol or a saltthereof can optionally be carried out in the presence of solvent, forexample an organic solvent or mixtures thereof with water, typically anether, such as tetrahydrofuran, dioxane, diethyl ether; a chlorinatedsolvent, such as dichloromethane, dichloroethane, tetrachloroethylene,chlorobenzene or dichlorobenzene; an alkanol, such as methanol, ethanolor isopropanol, or a mixture of two or more, preferably two or three, ofsaid solvents or with water. Particularly preferred are the reactionscarried out in alcohols, more particularly in ethanol or a water/ethanolmixture.

The reaction can be carried out at a temperature approx. ranging from 0°C. to the reflux temperature of the reaction mixture, preferably from25° C. to 50° C.

A compound of formula (II), wherein X is ═CO and R is a OR₁, group, asdefined above, which can optionally be isolated, can be obtained byreacting p-cresol, or a salt thereof, and a cinnamic acid derivative offormula (IX). The reaction, which can be schematized as follows

is preferably carried out in the presence of a basic agent,substantially as reported above as regards the reaction between acompound of formula (VIII) and p-creosol, or a salt thereof.

A compound of formula (III) wherein Y is hydroxy and Z is hydrogen canbe prepared by reducing a compound of formula (X)

wherein X and R are as defined above, with an alkali or alkaline-earthmetal borohydride, according to known methods.

A compound of formula (III) wherein Y, being as defined above, is otherthan hydroxy and Z is hydrogen or Y and Z, taken together complete adouble bond, can be obtained from a compound of formula (III) wherein Yis hydroxy and Z is hydrogen according to known methods.

A compound of formula (X), wherein X is —CH₂— and R is —N(isopropyl)₂can be obtained for instance according to Izvestiya Akademii Nauk SSSR,Seriya Khimicheskaya (1966), (4), 752-3. A compound of formula (X),wherein X is ═CO and R is —N(isopropyl)₂ can be obtained for instanceaccording to Tetrahedron Letters, ((2003) 44(43), 7957-9. A compound offormula (X), wherein X is ═CO and R is —OR₁, wherein R₁ is as definedabove, is a commercially available product or easily obtainabletherefrom. The compounds of formula (VI), (VII), (VIII) and (IX) areusual reagents or are anyway obtainable with known methods fromcommercially available products.

A compound of formula (II)

in which when X is —CH₂— then R is —N(isopropyl)₂; or when X is ═CO thenR is —N(isopropyl)₂ or —OR₁, wherein R₁ is an aryl or a straight orbranched C₁-C₆ alkyl group, optionally substituted with phenyl, is anovel compound and is a further object of the present invention.

Examples of preferred compounds of formula (II) are:

-   diisopropyl-(3-phenyl-3-p-tolyloxy-propyl)-amine;-   diisopropyl-(3-phenyl-3-p-tolyloxy-propyl)-amide; and-   methyl (3-phenyl-3-p-tolyloxy)-propionate.

The following examples illustrate the invention.

EXAMPLE 1 Preparation of p-tolyloxy-benzyl ether (VI)

A three-necked round-bottom flask equipped with condenser, magneticstirrer, thermometer, is loaded with p-cresol (100 g; 0.925 mol) andtetrahydrofuran (300 ml) under nitrogen stream. Sodium carbonate (166 g;1.20 mol) is added, keeping the suspension under stirring. The resultingmixture is then refluxed while benzyl chloride (158.1 g; 0.925 mol) isdropped therein in 30 minutes. After 18 hours, water is added (300 ml),the phases are separated and the aqueous phase is extracted with toluene(3×200 ml). The combined organic phases are dried over sodium sulfateand evaporated to dryness. 156.1 g of p-tolyloxy-benzyl ether areobtained as a solid crude, which is dried under vacuum at 50° C.

¹HNMR (300 MHz, CDCl₃): δ (ppm) 7.49-7.31 (m, 5H), 7.12 (d, 2H,), 6.91(d, 2H), 5.07 (s, 2H), 2.29 (s, 3H)

EXAMPLE 2 Diisopropyl-(3-phenyl-3-p-tolyloxy-propyl)-amine [(II) X isCH₂; R is N(isopropyl)₂]

A three-necked round-bottom flask equipped with condenser, magneticstirrer, thermometer, is loaded under nitrogen stream withp-tolyloxy-benzyl ether (11.2 g; 0.0589 mol), tetramethylenediamine (6.8g; 0.0589 mol) and tetrahydrofuran (50 ml), then cooled to 15° C. understirring. A 2.5 M solution of butyl lithium (24 ml 0.0589 mol) in hexaneis dropped therein, keeping the temperature below 0° C. After completionof the addition, temperature is kept at 0° C. for a further hour and asolution of chloroethyl diisopropylamine (9.6 g; 0.0589 mol) intetrahydrofuran (10 ml) is added. The mixture is left to warm to roomtemperature, then after an hour is poured in an ammonium chloridesaturated solution (50 ml), the phases are separated and the aqueousphase is extracted with toluene (3×30 ml). The combined organic phasesare dried over sodium sulfate and evaporated to dryness. The resultingdiisopropyl-(3-phenyl-3-p-tolyloxy-propyl)-amine is purified by flashchromatography. 9.9 g of product, as a pale yellow oil, are obtained.

¹HNMR (300 MHz, CDCl₃): δ (ppm) 7.36-7.17 (m, 5H), 6.96 (d, 2H), 6.74(d, 2H), 5.22 (dd, 1H), 3.05 (m, 2H), 2.65 (m, 2H), 2.21 (s, 3H),2.15-1.85 (m, 2H), 1.0 (m, 12H).

EXAMPLE 3 Tolterodine Free Base fromdiisopropyl-(3-phenyl-3-p-tolyloxy-propyl)-amine [from (II) wherein X isCH₂ and R is N(isopropyl)₂]

A three-necked round-bottom flask equipped with condenser, mechanicalstirrer, thermometer, is loaded withdiisopropyl-(3-phenyl-3-p-tolyloxy-propyl)-amine (1.0 g; 0.0031 mol) andpolyphosphoric acid (16.5 g). After three hours under stirring at roomtemperature, the reaction is completed. The reaction mixture is pouredin ice/water (10 g), alkalinized to pH 9-10 with NaOH 50% w/w and leftunder stirring for 30 minutes, then diluted with toluene (30 ml). Thephases are separated and the aqueous phase is extracted with toluene(2×30 ml). The combined organic phases are dried over sodium sulfate andevaporated to dryness. The resulting solid is crystallized from hexane(3 ml), filtered and dried under vacuum at 50° C. in a static dryer, toobtain 0.53 g of product.

EXAMPLE 4 Preparation ofdiisopropyl-(3-phenyl-3-p-tolyloxy-propyl)-amide. [(II) wherein X is COand R is N(isopropyl)₂]

A 1M solution of sodium ethoxide in ethanol (6.6 ml) under nitrogenpressure and cooled to 0° C., is slowly added dropwise with p-cresol(6.6 mmol, 0.72 g). After completion of the addition, the mixture isreacted for 15′ at room temperature, then added dropwise with in asolution of diisopropyl-(3-phenyl-3-bromine-propyl)-amide (VIII) (6.6mmol, 2.0 g) at room temperature checking that temperature does notexceed 30° C. The mixture is reacted for 4 h. The completion of thereaction is checked by HPLC, the mixture is acidified with acetic acidto pH 6-7 and the solvent is distilled off under reduced pressure. Theresulting oil is dissolved in methylene chloride (5.0 ml) and washedwith water (3×5 ml). The separated organic phase is then dried oversodium sulfate and the solvent is evaporated off under reduced pressure.The resulting pale yellow oil is purified by flash chromatography(hexane/ethyl acetate 8:2) to yield 0.5 g of product.

Following the same procedure, starting from a compound of formula (IX)in which R₁ is CH₃, methyl (3-phenyl-3-p-tolyloxy)-propionate isobtained [(II) wherein X is ═CO and R is —OCH₃].

EXAMPLE 5 Preparation of3-(2-hydroxy-5-methyl-phenyl)-N,N-diisopropyl-3-phenyl-propionamide (IV)[from (II) wherein X is CO and R is N(isopropyl)₂]

A three-necked round-bottom flask equipped with condenser, mechanicalstirrer, thermometer, is loaded withN,N-diisopropyl-3-phenyl-3-p-tolyloxy-propionamide (1.0 g; 0.0029 mol)and polyphosphoric acid (16.5 g). After four hours under stirring atroom temperature the reaction is completed. The reaction mixture ispoured in ice/water (10 g), alkalinized to pH 9-10 with NaOH 50% w/w andleft under stirring for 30 minutes, then diluted with toluene (30 ml).The phases are separated and the aqueous phase is extracted with toluene(2×30 ml). The combined organic phases are dried over sodium sulfate andevaporated to dryness. The resulting oil is purified by flashchromatography (hexane/ethyl acetate 7:3). 0.59 g of product, as a paleyellow oil, are obtained.

EXAMPLE 6 Preparation of 3-(2-hydroxy-5-methyl-phenyl)-3-phenylpropionicacid methyl ester (V). [from (II) wherein X is CO and R is OCH₃]

A three-necked round-bottom flask equipped with condenser, mechanicalstirrer, thermometer, is loaded with 3-p-tolyloxy-3-phenyl-propionicacid methyl ester (1.0 g; 0.0037 mol) and polyphosphoric acid (16.5 g).After four hours under stirring at room temperature the reaction iscompleted. The reaction mixture is poured in ice/water (10 g),alkalinized to pH 9-10 with NaOH 50% w/w and left under stirring for 30minutes, then diluted with toluene (30 ml). The phases are separated andthe aqueous phase is extracted with toluene (2×30 ml). The combinedorganic phases are dried over sodium sulfate and evaporated to dryness.The resulting oil is purified by flash chromatography (hexane/ethylacetate 7:3). 0.41 g of product, as a pale yellow oil, are obtained.

EXAMPLE 7 Preparation of tolterodine free base from3-(2-hydroxy-5-methyl-phenyl)-N,N-diisopropyl-3-phenyl-propionamide (IV)

A suspension of lithium aluminium hydride (3 g, 0.08 mols) in 350 ml ofanhydrous ether is added with 0.5 g of3-(2-hydroxy-5-methyl-phenyl)-N,N-diisopropyl-3-phenyl-propionamide inportions. The mixture is refluxed while stirring for 4 days. Afterwards,water is carefully added to destroy the lithium aluminium hydrideexcess, the mixture is acidified to pH 5 with acetic acid, the etherphase is separated and dried over sodium sulfate. The solvent isevaporated to obtain an oil which is purified by flash chromatography(eluent hexane-ethyl acetate 7:3). 0.1 g of tolterodine free base areobtained.

EXAMPLE 8 Preparation of tolterodine from3-(2-hydroxy-5-methyl-phenyl)-3-phenylpropionic acid methyl ester (V)

The compound 3-(2-hydroxy-5-methyl-phenyl)-3-phenylpropionic acid methylester (44 g 0.163 mol) is refluxed for 24 hours in a mixture consistingof 75 ml of methanol, 75 ml of acetone containing methyl iodide (25 g,0.175 mol) and potassium carbonate (13.75 g, 0.1 mol). Afterwards, thesolid is filtered off and the solvent is evaporated off. The residue isdissolved in ether and washed with water. The solvent is evaporated offto obtain 40 g of an oil which is redissolved in ether (75 ml) andslowly dropped in a solution of lithium aluminium hydride (5.6 g, 0.147g) in 150 ml of anhydrous ether. The mixture is left under stirringovernight. Afterwards the lithium aluminium hydride excess is destroyedwith water and 15% sodium hydroxide. The precipitate is filtered off andsolvent is evaporated off to obtain 35 g of an oil corresponding to thepropanol derivative. The resulting oil is dissolved in 50 ml ofchloroform containing 15 ml of pyridine and the mixture is cooled to−10° C. p-Toluenesulfonyl chloride (14 g, 0.07 mols) is dropped thereinand the mixture is reacted at −5/0° C. overnight, then poured inice/water. The organic phase is separated, washed with dilutedhydrochloric acid and distilled under vacuum at a temperature below 50°C. The resulting low-melting solid, that is the tosyl-derivative, isplaced in autoclave together with 50 ml of acetonitrile and 50 g ofdiisopropylamine. After heating the mixture at 80° C. for a week,volatile solvents are evaporated off. The residue is treated with 2Nsodium hydroxide and extracted with ether. The product is extracted fromthe ether phase with a 2N HCl solution. After further washings withether, the acidic phase is adjusted to basic pH with sodium hydroxideand the product is re-extracted with ether. The organic solution is thenevaporated to give an oil (20 g) corresponding to tolterodinephenol-protected as the methyl ether. Said oil is finally dissolved indichloromethane (75 ml), cooled to 0° C. and treated with a 1N solutionof boron tribromide in dichloromethane (32 ml 0.032 mols). The mixtureis kept one week under stirring in thermocryostat at temperaturesranging from 0 to 5° C. Afterwards, the solvent is evaporated off andthe residue is partitioned in a basic water/ether mixture. The organicsolvent is evaporated off to obtain an oil which is purified by flashchromatography (eluent hexane-ethyl acetate 7:3) and is tolterodine freebase.

EXAMPLE 9 Tolterodine free base fromdiisopropyl-(3-phenyl-3-hydroxy-propyl)-amine [from (III) wherein X isCH₂ and R is N(isopropyl)₂]

A three-necked round-bottom flask equipped with condenser, mechanicalstirrer, thermometer, is loaded withdiisopropyl-(3-phenyl-3-hydroxy-propyl)-amine (1.0 g; 0.0042 mol),p-cresol (0.51 g; 0.0046 mol) and 60% aqueous sulphuric acid (16.5 g).After three hours under stirring at 40° C. temperature, the reaction iscompleted. The reaction mixture is poured in ice/water (10 g),alkalinized to pH 9-10 with NaOH 50% w/w and left under stirring for 30minutes, then diluted with toluene (30 ml). The phases are separated andthe aqueous phase is extracted with toluene (2×30 ml). The combinedorganic phases are dried over sodium sulfate and evaporated to dryness.The resulting solid is crystallized from hexane (3 ml), filtered anddried under vacuum at 50° C. in a static dryer, to obtain 1.1 g ofproduct. (yield.: 80%)

EXAMPLE 10 Preparation of3-(2-hydroxy-5-methyl-phenyl)-N,N-diisopropyl-3-phenyl-propionamide (IV)[from (III) wherein X is CO and R is N(isopropyl)₂]

A three-necked round-bottom flask equipped with condenser, mechanicalstirrer, thermometer, is loaded withN,N-diisopropyl-3-phenyl-3-hydroxy-propionamide (1.0 g; 0.0041 mol),p-cresol (0.48 g; 0.0044 mol) and polyphosphoric acid (16.5 g). Afterfive hours under stirring at room temperature the reaction is completed.The reaction mixture is poured in ice/water (10 g), alkalinized to pH9-10 with NaOH 50% w/w and left under stirring for 30 minutes, thendiluted with toluene (30 ml). The phases are separated and the aqueousphase is extracted with toluene (2×30 ml). The combined organic phasesare dried over sodium sulfate and evaporated to dryness. The resultingoil is purified by flash chromatography (hexane/ethyl acetate 7:3). 0.48g of product, as a pale yellow oil, are obtained.

Analogously starting from a compound of formula (III), wherein X is ═COand R is an —OR₁, group as defined above, a respective compound offormula (IV) can be obtained.

EXAMPLE 11 Tolterodine free base fromdiisopropyl-(3-phenyl-3-p-tolyloxy-propyl)-amine [from (II) wherein X isCH₂ and R is N(isopropyl)₂]

A three-necked round-bottom flask equipped with condenser, mechanicalstirrer, thermometer, is loaded withdiisopropyl-(3-phenyl-3-p-tolyloxy-propyl)-amine (10 g; 0.031 mol) and60% aqueous sulfuric acid (50 g). After three hours under stirring atroom temperature, the reaction is completed. The reaction mixture ispoured in ice/water (50 g), alkalinized to pH 9-10 with NaOH 50% w/w andleft under stirring for 30 minutes, then diluted with toluene (50 ml).The phases are separated and the aqueous phase is extracted with toluene(2×50 ml). The combined organic phases are dried over sodium sulfate andevaporated to dryness. The resulting solid is crystallized from hexane(30 ml), filtered and dried under vacuum at 50° C. in a static dryer, toobtain 8.2 g of product. (yield. 82%).

1. A compound of formula (II)

in which when X is —CH₂— then R is —N(isopropyl)₂; or when X is ═CO thenR is —N(isopropyl)₂ or —OR₁, wherein R₁ is an aryl or a straight orbranched C₁-C₆ alkyl group, optionally substituted with phenyl.
 2. Thecompound according to claim 1, which is selected from the groupconsisting of diisopropyl-(3-phenyl-3-p-tolyloxy-propyl)-amine;diisopropyl-(3-phenyl-3-p-tolyloxy-propyl)-amide; and methyl(3-phenyl-3-p-tolyloxy)-propionate.